Data on Tofacitinib for Severe COVID-19
Tofacitinib, a janus kinase inhibitor, has recently been implicated as a potential treatment for Covid-19-related pneumonia. A recent study demonstrated that Covid-19 pneumonia patients who received tofacitinib had significantly decreased rates of respiratory failure and death.1
Tofacitinib, which also goes by the brand name Xeljanz, has traditionally been used to treat rheumatoid/psoriatic arthritis as well as ulcerative colitis. The small-molecule drug was first discovered during a collaborative research effort by the National Institutes of Health and the large pharmaceutical company Pfizer. A study using mouse models of established arthritis showed that tofacitinib inhibited both janus kinase 1 (JAK1) and janus kinase 3 (JAK3), ultimately disrupting the JAK-STAT signaling pathway and suppressing the expression of inflammatory mediators.2 More specifically, the authors reported that the drug reduced induction of T-bet, a key coordinator of type 1 immune response, and mitigated Th1 cell proliferation.2 These properties made tofacitinib a prime candidate for the treatment of autoimmune conditions. The drug has also found use as a short-term immunosuppressant to prevent organ transplant rejection.3
Given tofacitinib’s anti-inflammatory properties, study authors Guimarães et al. sought to test the drug’s efficacy in mitigating the exaggerated respiratory inflammation which characterizes severe Covid-19.1 Such inflammation is caused by a number of factors – including interleukin-6 and tumor necrosis factor α.4 Given that tofacitinib has been shown to reduce the activity of interleukin-6 as well as decrease cytokine release by various helper T cells, researchers hypothesized that the small molecule would have a positive benefit when administered to patients with severe Covid-19 infections.
The study was conducted within the Hospital Israelita Albert Einstein in São Paulo, Brazil, and admitted patients 18 or older who had tested positive for Covid-19 with radiographic evidence of an ongoing pneumonic infection. Patients were split randomly into two groups: one which received 10mg of tofacitinib twice daily and one which received placebo at the same interval. It was found that the primary outcome – respiratory failure and/or death within 28 days – was reduced by approximately 11 percent for the group which received the drug. Moreover, mortality in the placebo group was around 5.5 percent, whereas mortality in the tofacitinib group was approximately 2.8 percent. These results were somewhat complicated by the fact that adverse events occurred in a slightly higher frequency in the tofacitinib group – for example, several patients discontinued the trial due to elevated aminotransferase levels and lymphopenia. Therefore, for some patients with pneumonic Covid-19, tofacitinib may be contraindicated, and intensive monitoring may be necessary for those taking the drug.
Given that these findings are the first to report the use of tofacitinib to treat patients with Covid-19-related pneumonia, more research is necessary to establish the safety, dosing, and overall efficacy of the drug. Moreover, the study conducted by Guimarães et al. was funded in part by Pfizer. Though the conflict of interest was declared, this fact does call into question potential biases that may have influenced the research outcome. Altogether, these accumulative considerations mean that tofacitinib is far from becoming a standard treatment for severe Covid-19, although its potential will continue to be explored.
References
1 Guimarães, P. O., Quirk, D., Furtado, R. H., Maia, L. N., Saraiva, J. F., Antunes, M. O., Kalil Filho, R., Junior, V. M., Soeiro, A. M., Tognon, A. P., Veiga, V. C., Martins, P. A., Moia, D., Sampaio, B. S., Assis, S., Soares, R., Piano, L., Castilho, K., Momesso, R., Monfardini, F., … STOP-COVID Trial Investigators (2021). Tofacitinib in Patients Hospitalized with Covid-19 Pneumonia. The New England Journal of Medicine, 385(5), 406–415. https://doi.org/10.1056/NEJMoa2101643
2 Ghoreschi, K., Jesson, M. I., Li, X., Lee, J. L., Ghosh, S., Alsup, J. W., Warner, J. D., Tanaka, M., Steward-Tharp, S. M., Gadina, M., Thomas, C. J., Minnerly, J. C., Storer, C. E., LaBranche, T. P., Radi, Z. A., Dowty, M. E., Head, R. D., Meyer, D. M., Kishore, N., & O’Shea, J. J. (2011). Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550). Journal of Immunology (Baltimore, Md. : 1950), 186(7), 4234–4243. https://doi.org/10.4049/jimmunol.1003668
3 Busque, S., Vincenti, F. G., Tedesco Silva, H., O’Connell, P. J., Yoshida, A., Friedewald, J. J., Steinberg, S. M., Budde, K., Broeders, E. N., Kim, Y. S., Hahn, C. M., Li, H., & Chan, G. (2018). Efficacy and Safety of a Tofacitinib-based Immunosuppressive Regimen After Kidney Transplantation: Results From a Long-term Extension Trial. Transplantation Direct, 4(9), e380. https://doi.org/10.1097/TXD.0000000000000819
4 Fajgenbaum, D. C., & June, C. H. (2020). Cytokine Storm. The New England Journal of Medicine, 383(23), 2255–2273. https://doi.org/10.1056/NEJMra2026131